Diabetes is a disease, which develops complications such as abnormalities of peripheral nerves and autonomic nerves, disease symptoms of eyes, feet and kidneys, vascular diseases or the like due to an increase in blood sugar caused by a decline in insulin secretion and functions.
It is known that diabetes is generally divided into two types: Type I and Type II. Type I often occurs to children mainly due to congenital factors and requires such patients to get an insulin injection throughout the whole lifetime due to a failure of pancreas in secreting insulin, and also maintain a blood sugar in an appropriate level through a diet therapy and periodical examination. Type II mainly occurs to adults in a state that an insulin secretion declines or an insulin resistance grows enough to prevent cells from reacting to insulin due to life styles such as dietary habits, lack of exercise, obesity, etc., as well as environmental factors, wherein this type of disease accounts for 90 to 95% of 285 million patients with diabetes worldwide. Patients with type II diabetes may adjust a blood sugar through a weight loss, healthy diet and exercise, but their symptoms deteriorate due to characteristics of this progressive disease. Thus, patients have no choice but to get an insulin shot and main symptoms are polyuria, thirst, lethargy, hyperorexia, weight loss, etc., caused by a high blood sugar.
As a drug used for treating diabetes, there are roughly insulin and an oral hypoglycemic agent. Type I diabetes uses an insulin injection, while type II diabetes uses the oral hypoglycemic agent alone or in combination with insulin. As the oral hypoglycemic agent in current use, there are sulfonylurea and meglitinide drugs for stimulating insulin secretion, biguanide (metformin) and thiazolidine dione (PPAR-γ) drugs for improving insulin sensitivity, an α-glucosidase inhibitor drug for inhibiting a digestion of carbohydrates, a DPP-4 inhibitor, which is an incretin-based preparation, an SGLT2 inhibitor for preventing glucose reabsorption, etc. Despite a prescription of such oral hypoglycemic agent, many patients find it difficult to reduce glycated hemoglobin down to a target level or less. Meanwhile, in a study on diabetes patients for adjusting vascular risk factors, only 37% of those participants were able to achieve a level of glycated hemoglobin at less than 7.0% (Saydah, S. H. et. al., J. Am. Med. Assoc. 2004, 291, 335-342). Also, existing oral hypoglycemic agents exhibit side effects such as gastroenteric trouble, hypoglycemia, weight gain, lactic acidosis, edema, cardiotoxicity and hepatotoxicity along with limited durability of medicinal effects. Thus, there still remains a medical demand in the oral hypoglycemic agent field, wherein it is urgent to develop a fast-acting therapeutic agent of a new mechanism, which has excellent efficacy and durability of medicinal effects, safety and good drug tolerance, in particular without causing hypoglycemia. Therefore, much attention has been paid to a development of SGLT2 inhibitors as an oral preparation of a new mechanism, wherein it is not related to insulin, but has appropriate efficacy while being capable of reducing a weight.
A sodium-glucose cotransporter (SGLT), which is a transporter serving to absorb glucose in our body, is divided into 6 subtypes and expressed in several regions of our body, wherein the SGLT1 is mainly expressed in intestines and kidneys, while the SGLT2 is mainly expressed in kidneys. Also, the SGLT1 has a high affinity with glucose, but has a low transportation ability, while the SGLT2 has a low affinity with glucose, but has a high transportation ability. Healthy people reabsorb 99% of glucose filtered from the glomerulus of kidney, while excreting only 1% or less thereof in urine, wherein such glucose is reabsorbed at a ratio of 90% and 10% by means of SGLT2 and SGLT1, respectively. However, patients with type II diabetes have a high degree of expression of SGLT1 and SGLT2, thus have an increase in glucose absorption by means of SGLT1 in intestines and in glucose reabsorption by means of SGLT1/2 in kidneys, which results in a factor for increasing a blood sugar. Thus, there has been a development in hypoglycemic agents of a new mechanism, wherein a blood sugar is normalized through an SGLT1/2 inhibition, so as to recover an insulin secretion of pancreas and improve an insulin resistance in muscle and liver.
Phloridzin is extracted from the bark of apple tree and is a substance first evaluated as an SGLT inhibitor, wherein it has an antidiabetic efficacy, but has a low oral absorptivity and is metabolized in intestinal tracts to cause gastroenteric troubles or diarrhea, such that it has not been developed yet as a drug. Also, T-1095 was developed in 1990's as an orally absorbed SGLT2 drug by Tanabe Seiyaku, but its development was stopped in a clinical phase II, and sergliflozin or remogliflozin, which were O-glocoside having a similar structure thereto, were stopped in a clinical phase II of development. A C-glucoside drug was started to be developed in order to avoid a metabolism by means of β-glucosidase, which was a weak point of the O-glucoside drug.
As Bristol-Myers Squibb launched a clinical test on dapagliflozin in 2004, many pharmaceutical companies started to develop a drug in this series. Then, such dapagliflozin got a first permission for marketing in Europe in 2012, after which canagliflozin (Johnson & Johnson, Mitsubishi Tanabe) received a first permission for marketing in the United States in 2013, and then dapagliflozin and empagliflozin (Boehringer-Ingelheim) did so in the U.S. while ipragliflozin (Astellas), luseogliflozin (Taisho) and tofogliflozin (Chugai) did so in Japan, respectively. Meanwhile, the SGLT1 is known to play an important role in absorption of glucose and galactose in small intestines as well as in reabsorption of glucose in kidney (Levin, R. J., Am. J. Clin. Nutr. 1994, 59(3), 690S-698S). Accordingly, it is thought that the absorption of glucose may be inhibited in small intestines and the reabsorption of glucose may be inhibited in kidney by means of SGLT1 inhibition, thus exhibiting an efficacy on blood sugar control. Thus, an SGLT1/2 dual inhibitor may become a novel mechanism for treating diabetes, wherein sotagliflozin, an SGLT1/2 dual inhibitor, is now in a clinical phase III for type I diabetes and in preparation for a clinical phase III for type II diabetes, while LIK-066, an SGLT1/2 dual inhibitor of Novartis, is now in a clinical phase II, too.